Genetic Polymorphisms in RANK and RANKL are Associated with Persistent Apical Periodontitis.

INTRODUCTION: The outcome of root canal treatment has been reported as intimately related to the host response. Genetic polymorphisms might be associated with apical periodontitis repair. The aim of this study was to evaluate the association between receptor activator of nuclear factor kappa B (RANK), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) genetic polymorphisms with persistent apical periodontitis (PAP) in Brazilian subjects. METHODS: Subjects with at least 1 year of follow-up after nonsurgical root canal therapy were recalled. Sixty-four subjects with signs/symptoms of PAP and 86 subjects with root canal-treated teeth exhibiting healthy periradicular tissues (healed) were included. Genomic DNA was extracted from saliva and used for RANK (rs3826620), RANKL (rs9594738), and OPG (rs2073618) genotyping by real-time exact tests, and odds ratio were implemented using Epi Info 3.5.2 (Centers for Disease Control and Prevention, Atlanta, GA). A logistic regression analysis was also performed using the time of follow-up as the covariate. All tests were performed with an established alpha of 0.05 (P = .05). RESULTS: An association between allele distribution and the polymorphism in RANK was observed. Subjects who carry the T allele had a lower risk of having PAP (P < .05). In RANKL polymorphism, the genotype distribution was statistically significant different between the PAP and healed groups (P = .05). The time of follow-up was associated with PAP (P < .05). In the logistic regression analysis using time as a covariant, RANK (P < .05) and RANKL (P < .05) were associated with PAP. The polymorphism rs2073618 in OPG was not associated with PAP (P > .05). CONCLUSIONS: These findings suggest that polymorphisms in RANK and RANKL genes are associated with PAP.

The Epithelial-Myeloid-Transition (EMyeT) of cancer cells as a wrongly perceived primary inflammatory process eventually progressing to a bone remodeling malignancy: the alternative pathway for Epithelial- Mesenchymal-Transition hypothesis (EMT)?

Cancer cells express multiple markers expressed by mesenchymal as well as myeloid cells in common and in addition specific markers of the myeloid lineages, especially those of dendritic cells, macrophages and preosteoclasts. It has also been possible to identify monocyte-macrophage gene clusters in cancer cell specimens as well as in cancer cell lines. Accordingly, like myeloid cells cancer cells often express pro-inflammatory cytokines, and consequently the carcinoma may be perceived by the organism as a primary inflammatory process comparable to the immune inflammatory reactions in the eye or in the case of arthritis. This would explain why a carcinoma may induce a certain alarm state in the organism by increasing a fatal sympathetic tone in the patient, supplying the carcinomas with nutrients at the cost of other requirements, inducing tolerance against the cancer cells mistaken as myeloid cells, provoking fibrosis and neoangiogenesis, and increasing inflammatory cells at the carcinoma site. This seemingly inflammatory process of Epithelial-Myeloid-Transition (EMyeT) is superimposed by the progression of part of the myeloid cancer cells to stages comparable to preosteoclasts and osteoclasts, and their development to metastasizing carcinomas often at the site of bone. This concept of carcinogenesis and malignant progression described here challenges the widely accepted EMT-hypotheses and could deliver the rationale for the various peculiar aspects of cancer and the variety of therapeutic antitumoral measures.

Genetic, Cellular and Molecular Aspects involved in Apical Periodontitis

Abstract The development, establishment and repair of apical periodontitis (AP) is dependent of several factors, which include host susceptibility, microbial infection, immune response, quality of root canal treatment and organism's ability to repair. The understanding of genetic contributions to the risk of developing AP and presenting persistent AP has been extensively explored in modern Endodontics. Thus, this article aims to provide a review of the literature regarding the biochemical mediators involved in immune response signaling, osteoclastogenesis and bone neoformation, as the genetic components involved in the development and repair of AP. A narrative review of the literature was performed through a PUBMED/MEDLINE search and a hand search of the major AP textbooks. The knowledge regarding the cells, receptors and molecules involved in the host's immune-inflammatory response during the progression of AP added to the knowledge of bone biology allows the identification of factors inherent to the host that can interfere both in the progression and in the repair of these lesions. The main outcomes of studies evaluated in the review that investigated the correlation between genetic polymorphisms and AP in the last five years, demonstrate that genetic factors of the individual are involved in the success of root canal treatment. The discussion of this review gives subsides that may help to glimpse the development of new therapies based on the identification of therapeutic targets and the development of materials and techniques aimed at acting at the molecular level for clinical, radiographic and histological success of root canal treatment.

Resumo O desenvolvimento, estabelecimento e reparo da periodontite apical (PA) depende de vários fatores, que incluem a susceptibilidade do hospedeiro, infecção microbiana, resposta imune, bem como a qualidade do tratamento do canal radicular e a capacidade de reparo do organismo. A compreensão das contribuições genéticas para o risco de desenvolver a PA e apresentar PA persistente tem sido extensivamente explorada na Endodontia moderna. Assim, este manuscrito pretende fornecer uma revisão da literatura em relação aos mediadores bioquímicos envolvidos na sinalização da resposta imune, osteoclastogênese e neoformação óssea, bem como os componentes genéticos envolvidos no desenvolvimento e reparo da PA. Uma revisão narrativa da literatura foi realizada através de uma pesquisa nas bases PUBMED/MEDLINE e uma pesquisa manual nos principais livros sobre a PA. O conhecimento sobre as células, receptores e moléculas envolvidas na resposta imuno-inflamatória do hospedeiro durante a progressão da PA somado ao conhecimento da biologia óssea, especialmente o papel dos osteoblastos, osteócitos e osteoclastos no turnover ósseo, permite a identificação de fatores inerentes ao hospedeiro que podem interferir tanto na progressão como no reparo destas lesões. Os principais resultados dos estudos avaliados na revisão que investigaram a correlação entre polimorfismos genéticos e PA, nos últimos cinco anos, demonstram que os fatores genéticos do indivíduo estão envolvidos no sucesso do tratamento do canal radicular. A discussão desta revisão fornece subsídios que podem ajudar a vislumbrar o desenvolvimento de novas terapias baseadas na identificação de alvos terapêuticos e no desenvolvimento de materiais e técnicas destinadas a atuar a nível molecular para o sucesso clínico, radiográfico e histológico do tratamento endodôntico.

Biomimetic whitlockite inorganic nanoparticles-mediated in situ remodeling and rapid bone regeneration.

Bone remodeling process relies on complex signaling pathway between osteoblasts and osteoclasts and control mechanisms to achieve homeostasis of their growth and differentiation. Despite previous achievements in understanding complicated signaling pathways between cells and bone extracellular matrices during bone remodeling process, a role of local ionic concentration remains to be elucidated. Here, we demonstrate that synthetic whitlockite (WH: Ca18Mg2(HPO4)2(PO4)12) nanoparticles can recapitulate early-stage of bone regeneration through stimulating osteogenic differentiation, prohibiting osteoclastic activity, and transforming into mechanically enhanced hydroxyapatite (HAP)-neo bone tissues by continuous supply of PO43- and Mg2+ under physiological conditions. In addition, based on their structural analysis, the dynamic phase transformation from WH into HAP contributed as a key factor for rapid bone regeneration with denser hierarchical neo-bone structure. Our findings suggest a groundbreaking concept of 'living bone minerals' that actively communicate with the surrounding system to induce self-healing, while previous notions about bone minerals have been limited to passive products of cellular mineralization.

Prediction of stress shielding around an orthopedic screw: using stress and strain energy density as mechanical stimuli.

Using finite element analysis, a parametric study was developed to compare stress and strain energy density (SED), in order to determine which stimuli might be better for predicting stress shielding in bone-screw models. Defined stimuli transfer parameters demonstrated that stress and SED (strong candidates for initiating the bone remodeling process) are transferred distinctively between an implant and bone. While small diameter angled threads increased transfer of both stimuli, reducing the screw's elastic modulus resulted in an increased transfer of stress; and unexpected decrease in SED, indicating that SED should be carefully examined in the context of future bone-screw models.